Our studies and those of others have shown that for many normal cell types, stressors that produce DNA damage (such as radiation and chemotherapy) induce a response that includes the robust secretion of specific extracellular effector proteins that we term the DNA Damage Secretory Program (DDSP). The DDSP includes a spectrum of autocrine and paracrine-acting proinflammatory cytokines, proteases and mitogenic growth factors that can promote tumor growth, inhibit cellular differentiation, and enhance angiogenesis. Further, constituents derived from damaged fibroblasts can also induce an epithelial to mesenchymal transition (EMT) in carcinoma cells accompanied by enhanced resistance to chemotherapeutics. Thus, the reaction of any tumor cell to genotoxic stress may depend on both intrinsic damage response capabilities and context dictated by the amalgam of cellular interactions in the tumor microenvironment (TME). In this proposal, we will conduct pre-clinical and clinical trials designed to test the hypothesis that inhibiting components of the microenvironment-derived DNA damage secretory program will enhance the responses of prostate tumors to commonly used genotoxic cancer treatments. We propose two aims: Aim 1: To evaluate the effects of inhibiting key regulators and effectors of the microenvironment DNA Damage Secretory Program on therapy responses in preclinical models of prostate cancer. Rationale: defining convergent and divergent influences of master regulators and specific effectors of the microenvironment DDSP will inform pharmacological strategies to maximally inhibit the DDSP, reduce side-effects, and improve therapy responses. Aim 2: To conduct a Phase l-II trial evaluating the clinical effect of inhibiting master regulators and specific effectors of the DNA Damage Secretory Program in augmenting genotoxic chemotherapy in men with metastatic CRPC. Rationale: metastatic prostate cancer is essentially incurable. Augmenting chemotherapy responses by suppressing microenvironment resistance mechanisms has the potential to improve therapeutic outcomes produced by commonly used genotoxic chemotherapy.